The clinical efficacy of combinatorial therapy of EGFR-TKI and crizotinib in overcoming MET amplification-mediated resistance from prior EGFR-TKI therapy
The clinical efficacy of combinatorial therapy of EGFR-TKI and crizotinib in overcoming MET amplification-mediated resistance from prior EGFR-TKI therapy
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EGFR-TKI 和克唑替尼联合治疗在克服既往 EGFR-TKI 治疗中 MET 扩增介导的耐药性方面的临床疗效
DOI：
10.1016/j.lungcan.2020.06.003
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发表时间：
2020-08-01
期刊：
影响因子：
5.3
通讯作者：
He, Yong
中科院分区：
文献类型：
--
作者：
Wang, Yubo;Tian, Panwen;He, Yong
背景：MET扩增是EGFR酪氨酸激酶抑制剂（TKI）耐药的EGFR非依赖性机制之一。EGFR-TKI和克唑替尼的联合治疗已被探索为通过同时靶向EGFR和MET途径来克服耐药性的策略;然而，对于具有最大益处的最佳联合方案仍不存在共识。对从11名肺腺癌患者获得的临床和测序数据进行了回顾性分析，这些患者在从既往EGFR-1基因突变进展时获得了MET扩增。TKI治疗，并接受了EGFR-TKI和crizotinib.Results的组合：：获得性MET扩增检测到4和7例患者从一线吉非替尼和二线奥希替尼，分别进展。分别有6例和5例患者接受了第一代（吉非替尼、厄洛替尼或埃克替尼）或第三代（奥希替尼）EGFR-TKI和克唑替尼联合治疗。9例患者获得部分缓解，总缓解率为81.8%。队列的中位无进展生存期为5.8个月。此外，对9例患者的获得性耐药机制进行分析，从3例第一代EGFR-TKI和克唑替尼治疗后进展的患者中发现了EGFR T790 M，而从奥希替尼和克唑替尼治疗后进展的各1例患者中检测到EGFR T790 M/trans-C797 S和L718 Q、EGFR G724 S和CCDC 6-RET融合。损失的MET扩增也观察到在大多数的患者在进展从combinationtherapy.Conclusions：：我们的研究提供了临床证据的组合方案与第一代或第三代EGFR-TKI和克唑替尼后出现的MET扩增介导的EGFR-TKI耐药EGFR突变型NSCLC患者的疗效。
Background: : MET amplification is one of the EGFR-independent mechanisms of EGFR tyrosine kinase inhibitor (TKI) resistance. Combinatorial therapy of EGFR-TKI and crizotinib has been explored as a strategy to overcome resistance by simultaneously targeting both EGFR and MET pathways; however, no consensus still exists on the optimal combination regimen with the most benefit.Methods: : Retrospective analysis was performed on the clinical and sequencing data obtained from eleven patients with lung adenocarcinoma who acquired MET amplification at progression from prior EGFR-TKI therapy and received a combination of EGFR-TKI and crizotinib.Results: : Acquired MET amplification was detected in four and seven patients who progressed from first-line gefitinib and second-line osimertinib, respectively. Six and five patients received a combination of either firstgeneration (gefitinib, erlotinib, or icotinib) or third-generation (osimertinib) EGFR-TKI and crizotinib, respectively. Nine patients achieved partial response, resulting in an overall response rate of 81.8 %. The median progression-free survival of the cohort was 5.8 months. Moreover, analysis of acquired resistance mechanisms from nine patients identified EGFR T790M from three patients who progressed from first-generation EGFR-TKI and crizotinib, while EGFR T790 M/trans-C797S and L718Q, EGFR G724S, and CCDC6-RET fusion were detected from one patient each who progressed from osimertinib and crizotinib regimen. Loss of MET amplification was also observed in a majority of the patients at progression from the combination therapy.Conclusions: : Our study provides clinical evidence of the efficacy of combinatorial regimen with either first- or third-generation EGFR-TKI and crizotinib after the emergence of MET amplification-mediated EGFR-TKI resistance in patients with EGFR-mutant NSCLC.